Article

PIAS proteins promote SUMO-1 conjugation to STAT1

Department of Chemistry, University of Helsinki, Helsinki, Uusimaa, Finland
Blood (Impact Factor: 10.43). 12/2003; 102(9):3311-3. DOI: 10.1182/blood-2002-12-3816
Source: PubMed

ABSTRACT Signal transducer and activator of transcription 1 (STAT1) is a critical mediator of interferon-gamma (IFN-gamma)-induced transcription that is regulated through posttranslational modifications and through transacting proteins such as protein inhibitor of activated STAT1 (PIAS1). PIAS proteins have been shown to function as E3-type small ubiquitin-like modifier (SUMO) ligases, and sumoylation has been identified as a modulatory mechanism for several transcription factors. Here we show that STAT1 is subject to SUMO-1 modification, and sumoylation occurs in vivo and in vitro at a single, evolutionary conserved amino acid residue Lys703. Members of the PIAS family of proteins were found to strongly stimulate sumoylation of STAT1. Furthermore, activation of STAT1 by IFN-gamma or pervanadate induced SUMO-1 conjugation. Mutation of Lys703 in STAT1 resulted in increased IFN-gamma-mediated transactivation, suggesting a negative regulatory function for sumoylation. These results indicate that STAT1 is covalently modified by SUMO-1 in cytokine signaling and that PIAS proteins promote SUMO-1 conjugation to STAT1.

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    • "Compared with SUMOylation of wild-type STAT5, SUMOylation of single mutants or combined mutants remained unchanged, suggesting that these lysine residues are not involved in SUMOylation of STAT5 (Figure S6A). Previous studies indicate that STAT1 is SUMOylated at lysine 703, close to tyrosine 701 (Rogers et al., 2003; Song et al., 2006; Ungureanu et al., 2003). Indeed, STAT5A contains two lysines at 696 and 700, close to tyrosine 694 (Figure 5A). "
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    • "Whereas there is debate on whether STAT1 undergoes lysine methylation [76] [77] [78], modification of K703 with the small Ubiquitin-like modifier SUMO1 was frequently observed in IFN-treated cells [79] [80] [81] [82]. Similar to acetylation, sumoylation of STAT1 antagonizes its phosphorylation at Y701 and subsequent signaling (Figure 4). "
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    • "These results indicate that PRMT1 regulates PIAS1-mediated repression of STAT1 target genes at the chromatin level by allowing promoter recruitment of PIAS1, which subsequently diminishes promoter association of STAT1. Recent studies suggested a role of PIAS1-mediated sumoylation of STAT1 in the repression of STAT1 signaling (Ungureanu et al. 2003, 2005). We asked whether PRMT1 has an impact on the sumoylation of STAT1. "
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